Matthew Whitby
Genetic recombination and DNA repair in eukaryotes
Co-workers: Sonali Bhattacharjee, Victoria Folkyte, Saikat Nandi, Sevil Sofueva, Weili Sun, Fikret Osman, Alexander Lorenz, Roland Steinacher, Vincent Mason
Homologous recombination (HR) repairs DNA double-strand breaks (DSBs) and damaged replication forks, and as such is critical for maintaining genome integrity. However, it injudicious use can result in potentially harmful genome rearrangements. Cells therefore have to carefully control when and how HR is used. The importance of this to human health is underscored by a number of diseases such as familial breast cancer, Fanconi anaemia, and Bloom's and Werner's syndromes that are linked to dysfunctional HR. These diseases variously manifest clinical features such as cancer proneness, immunodeficiency, developmental problems and premature ageing. HR is also essential in most eukaryotes for promoting the correct segregation of homologous chromosomes during the first meiotic division. A failure in HR in the human oocyte can result in aneuploidy, which is a factor in many spontaneous pregnancy losses, and in the case of trisomy 21 results in Down's syndrome.
My group is interested in the molecular mechanisms that govern homologous recombination in mitotic and meiotic cells. In particular we want to know: the mechanism by which homologousrecombination repairs DSBs and broken replication forks; what factors determine whether recombination acts at stalled replication forks; and what determines pathway choice duringDSB repair. In relationship to these questions we are currently using the fission yeast Schizosaccharomyces pombe as a model system to decipher the molecular mechanisms andmodes of governance of a number of key proteins, including Fbh1, Fml1, Rqh1 and Mus81-Eme1, which have pro- and/or anti-recombinogenic activities.
Publications
- Sun, W., Nandi, S., Osman, F., Ahn, J., Jakovleska, J., Lorenz, L. and Whitby, M.C. (2008) The fission yeast FANCM ortholog Fml1 promotes recombination at stalled replication forks and limits crossing over during double-strand break repair. Mol. Cell, 32, 118-128
- Gaskell, L.J., Osman, F., Gilbert, R.J. and Whitby, M.C. (2007) Mus81 cleavage of Holliday junctions: a failsafe for processing meiotic recombination intermediates? EMBO J. 26, 1891-1901
- Osman, F. and Whitby, M.C. (2007) Exploring the roles of Mus81-Eme1/Mms4 at perturbed replication forks. DNA Repair (Amst) 6, 1004-1017
- Osman F., Dixon J., Barr A.R. and Whitby M.C. (2005) The F-box DNA helicase Fbh1 prevents Rhp51-dependent recombination without mediator proteins. Mol. Cell. Biol. 25, 8084-8096
- Ahn J., Osman, F. and Whitby M.C. (2005) Replication fork blockage by RTS1 at an ectopic site promotes recombination in fission yeast. EMBO J. 24, 2011-2023
More Publications...
Research Images
Figure 1: DSB repair pathways in fission yeast
Figure 2: Visualizing the recruitment of a recombination protein (Rad22) to a replication fork blocked at a site-specific barrier in a live cell. Rad22 is tagged with yellow fluorescent protein (YFP), and the replication fork barrier is marked by the LacI repressor fused to cyan fluorescent protein (CFP)
Figure 3: Replication fork blockage at a site-specific barrier detected by native two-dimensional gel electrophoresis
Contact:matthew.whitby@bioch.ox.ac.uk
Graduate Student and Postdoctoral Positions: Enquiries with CV welcome